Background: We evaluated the safety and efficacy of the combo of T-VEC, the first FDA-approved oncolytic immunotherapy that enhances systemic antitumor immune responses, and Pembro, an immune checkpoint inhibitor against programmed death receptor-1 (PD-1), in pts with R/M HNSCC. Methods: Pts were eligible for enrollment if they had histologically confirmed R/M HNSCC unsuitable for curative resection or radiotherapy, and platinum-refractory and injectable disease. T-VEC was injected intralesionally at a dose of up to 8.0 mL of 10⁶ PFU/mL on day 1. After 3 weeks, subsequent doses of up to 8.0 mL of 10⁸ PFU/mL were administered every 3 weeks (Q3W). Pembro was administered intravenously at a dose of 200 mg Q3W. The primary objective was to evaluate safety, as assessed by the incidence of dose limiting toxicity (DLT). Key secondary objectives were objective response rate (ORR), best overall response per immune-related RECIST, and long-term safety. Results: 36 pts were enrolled and treated: 28 (77.8%) had confirmed PD-L1-positive tumor; 5 (13.9%) were HPV-positive and 13 (36.1%) were HPV-negative, with 18 (50%) unknown. One (6.3%) DLT, fatal arterial hemorrhage, was observed among 16 DLT-evaluable pts. Overall, 24/36 (66.7%) pts had grade 3 or higher treatment-emergent adverse events (TEAEs): 5 (13.9%) and 3 (8.3%) pts had TEAEs related to T-VEC and Pembro; 2 (5.6%) and 1 (2.8%) pt discontinued treatment due to T-VEC- and Pembro-related TEAEs, respectively. The most common TEAEs were pyrexia (36.1%), dyspnea (33.3%), and fatigue (25.0%). 24/36 (66.7%) pts had serious AEs. 7 deaths were reported during the study, 1 of which was related to T-VEC (the DLT pt) and none to Pembro. The ORR was 16.7% (6/36 pts; 5 PD-L1-positive; 95% CI, 6.4–32.8), and the disease control rate (objective response/stable disease) was 38.9% (14/36 pts; 11 PD-L1-positive; 95% CI, 23.1–56.5). Conclusions: The combo demonstrated a manageable safety profile. Preliminary ORR showed clinical activity in R/M HNSCC. Further follow-up is ongoing for PFS/OS. Clinical trial information: NCT02626000